Nerves can be damaged either through trauma or disease. Nerves from the peripheral nervous system (PNS) have significantly greater capacity to regenerate and reinnervate their original targets after injury, as compared to nerves from central nervous system (CNS). The successful regeneration of PNS neurons requires a number of intrinsic and extrinsic factors, as well as, a permissive microenvironment for axonal regrowth. Bosse, E. Extrinsic cellular and molecular mediators of peripheral axonal regeneration, Cell Tissue Res. 349, 5-14 (2012). Among the numerous growth factors able to induce nerve regeneration, the family of vascular endothelial growth factors (VEGF), has been implicated as a potent mediator of developmental neurogenesis and adult nerve regeneration. Carmeliet, P. & Carmen Rde, A, VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration, Cellular and Molecular Life Sciences: CMLS 70, 1763-1778 (2013); Licht, T. & Keshet, E., Delineating multiple functions of VEGF-A in the adult brain, Cellular and Molecular Life Sciences: CMLS 70, 1727-1737 (2013); Mackenzie, F. & Ruhrberg, C., Diverse roles for VEGF-A in the nervous system, Development 139, 1371-1380 (2012).
VEGF-A, is a well-characterized and potent angiogenic factor, but is also a strong inducer of nerve growth. Several studies have demonstrated that both VEGF-A and -B are expressed during peripheral nerve injury. Li, X., Kumar et al., Complicated life, complicated VEGF-B, Trends Mol. Med. 18, 119-127 (2012); and Carmeliet, P. & Carmen Rde, A, VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration, Cellular and Molecular Life Sciences: CMLS 70, 1763-1778 (2013) In the setting of injury, VEGF-B plays a role in cell survival, nerve protection and growth. Li, X., Kumar et al. (2012); and Dhondt, J. et al., Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons, FASEB J. 25, 1461-1473 (2011).
The survival effect of VEGF-B on brain cortical neurons, retinal neurons and motor neurons in the spinal cord, is indicative of its pleiotropic role. Li, X., Kumar et al., Trends Mol. Med. 18, 119-127 (2012). VEGF-B treatment has also been found to reduce stroke volume in a middle cerebral artery ligation model and increased survival of retinal ganglion cells in an optic nerve crush injury model, and VEGF-B knockout mice suffered severe strokes and exacerbated retinal ganglion cell death in both injury models. Li, Y. et al., VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats, The Journal of Clinical Investigation 118, 913-923 (2008); Sun, Y. et al., Increased severity of cerebral ischemic injury in vascular endothelial growth factor-B-deficient mice, J. Cereb. Blood Flow Metab. 24, 1146-1152 (2004); Greenberg, D. A. & Jin, K., Vascular endothelial growth factors (VEGFs) and stroke, Cellular and Molecular Life Sciences:CMLS 70, 1753-1761 (2013).
VEGF-B has also been used with promising results in Parkinson's disease and amyotrophic lateral sclerosis models. Falk, T. et al., Vascular endothelial growth factor-B is neuroprotective in an in vivo rat model of Parkinson's disease, Neurosci. Lett. 496, 43-47 (2011); Poesen, K. et al., Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration, J. Neurosci. 28, 10451-10459 (2008).
Given the ability of VEGF-B to regulate both vascular endothelial cells (angiogenesis) as well as axonal growth and survival following injury, it is unclear whether VEGF-B exerts its effects on nerve regeneration through the increase in blood supply, or through direct effects on nerve tissue. Nash, A. D. et al., The biology of vascular endothelial growth factor-B (VEGF-B), Pulm. Pharmacol. Ther. 19, 61-69 (2006); Sun, Y. et al., Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: evidence from knockout mice and growth factor administration, Dev. Biol. 289, 329-335 (2006). Indeed, specific studies on its role on peripheral neurons independent of its vascular role are lacking. We have previously reported that VEGF-A can stimulate trigeminal neuronal cell growth and enhance cornea nerve regeneration, resulting in anatomical and functional recovery of peripheral injured nerves independently of its angiogenic effects. Pan, Z., Fukuoka et al., Vascular endothelial growth factor promotes anatomical and functional recovery of injured peripheral nerves in the avascular cornea, FASEB J, 27, 2756-2767 (2013).